Injectable Liquid Paracetamol Formulation

ABSTRACT

The invention relates to an aqueous paracetamol solution for administration by means of infusion with a pH of between 4.5 and 6, containing at least one substance that can react with fenolates to produce the O-derivatives thereofor other co-ordination compounds. The injectable paracetamol solution has high stability, does not become coloured over time and has a minimum impurity content.

FIELD OF THE INVENTION

The present invention relates to an injectable liquid paracetamolcomposition according to the preamble of claim 1.

BACKGROUND OF THE INVENTION

Paracetamol (n-acetyl-4-aminophenol) is an active ingredient that hasbeen widely used in the last 4 decades in pharmaceutical preparationsdue to its activity as an analgesic and an antipyretic which wasintroduced by Von Mering in 1893. It is further well tolerated by humanbeings and does not alter the acid-base equilibrium, therefore it iswidely used to relive pain both in adults and in children and in theelderly. A large number of pharmaceutical preparations to beadministered orally or even topically are known. However, it isdifficult to obtain a pharmaceutical preparation for injection andparticularly, a ready-to-use solution for intravenous perfusion, due tothe fact that paracetamol is not very soluble in water and its solutionsin aqueous medium are unstable in the presence of oxygen and/or light,being decomposed through a plurality of degradation pathways which arewell known and are described for example in the article “Stability ofaqueous solutions of N-acetyl-p-aminophenol”, by K. T. Koshy and J. L.Lach, J. Pharmaceutical Sciences, Vol 50 (2) (February 1961), p.113-118. This instability in aqueous medium is shown by the appearanceof degradation substances causing a coloring in the solution. Thedifferent substances causing the coloring of the solution includebenzoquinoimines which are hepatotoxic in humans.

However, the development of color in pharmaceutical solutions andespecially in injectable formulations which must be completelytransparent involves a serious problem, because the presence of saidcolor is indicative of the existence of unwanted compounds in theformulation and therefore leads to the rejection of the injectableproduct without being used.

One of the causes of paracetamol degradation is based on chemicaloxidation reactions in which the oxygen present in the solution is themain precursor of this degradation. The secondary cause of degradationmay be the deacetylation of the amino group generating p-aminophenolwhich is also quickly degraded producing p-benzoquinoneimine. Thisdeacetylation takes places both at acid pH and (much faster) at basic pHonce the phenolate form is present.

In vivo, most of the paracetamol is metabolized through the formation ofthese phenolate form derivatives, mainly through the gluconatedderivative and through the sulfonated derivative:

Obtaining stable paracetamol solutions in aqueous medium can be solvedby means of several joint actions.

1) Establishing an optimal pH in which the formation of 4-aminophenol isprevented or minimized, as has been indicated by K. Thomas Koshy and JonL. Lach in the previous indicated reference “Stability of aqueoussolutions of N-acetyl-p-aminophenol”, J. of Phar. Sci., Vol 50 No. 2(1961), 113-118, the hydrolysis of the acetate group of paracetamol isminimized between pH=4.5 and pH 6.0.

2) Preventing the presence of oxygen in solution. This action isdescribed in Spanish patent no. 2,201,316, from the validation in Spainof European patent EP 858,329 B1, issued to Pharmatop SCR. This documentdiscloses a process whereby paracetamol oxidation is prevented by meansof eliminating the main element activating the reaction, oxygen, withnitrogen bubbling. By further keeping the solution in a completelyhermetic bottle, the stability of paracetamol in solution is ensured forlong time periods, with minimal impurity levels and the total absence ofcolor in the solution. It must be deduced by the characteristics of theSCR Pharmatop product that its must be kept in suitable bottlespreventing the incorporation of oxygen into the solution and thereforethese solutions cannot be stored in individual oxygen-permeable bottlessuch as plastic materials.

The joint action on the two previous factors allows obtaining a stableparacetamol solution which does not develop color for a long timeperiod.

International patent publication WO2004/071502 A1, issued toNguyen-Xuan, describes a paracetamol formulation containing a bufferagent with a pKa between 4.5 and 6.5, an isotonic agent and aparacetamol dimer. The stability of paracetamol in solution isattributed to the presence of the paracetamol dimer of formula Iproduced in situ by treatment of the solution with a temperature between100° C. and 130° C. for at least 5 minutes. This formulation does notneed the elimination of oxygen and can be stored in some plasticmaterials. However, it has the following drawbacks:

-   -   1. Since it does not contain factors preventing the oxidation of        paracetamol, polymerization impurities such as the mentioned        dimer are generated over time, providing color to the solution        and turning it into a product that is unsafe in its use because        at the time of its use it is not possible to know if the color        is from the formation of paracetamol polymers or        benzoquinoneimines or of other substances with an unknown        origin.    -   2. The stability of these solutions is reduced when they are        stored in plastic materials such as PVC, the composition of        which does not use antioxidants. In other words, they must be        stored in plastic materials such as polypropylene, polyolefins,        polyethylene, polyethylene vinyl acetate, containing        antioxidants and preventing or making the entrance of oxygen        into the solution difficult. These materials typically contain        one of several of the following antioxidants:

-   1.—butylhydroxytoluene,

-   2.—Pentaerythrityl    tetrakis(3,5-di-tert-butyl-4-hydroxyphenyl)propionate;

-   3.—1,3,5-tris(3,5-di-tert-butyl-4-hydroxybenzyl)-s-triazine-2,4,6(1H,3H,5H)-trione;

-   4.—octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate;

-   5.—ethylenebis[3,3-bis[3-(1,1-dimethylethyl)-4-hydroxyphenyl]butanoate];

-   6.—dioctadecyl disulfide;

-   7.—2,2′,2′,6,6′,6″-hexa-tert-butyl-4,4′,4″-[(2,4,6-trimethyl-1,3,5-benzenetriyl)trismethylene]triphenol;

-   8.—2,2′-bis(octadecyloxy)-5,5′-spirobi[1,3,2-dioxaphosphinane];

-   9.—didodecyl 3,3′-thiodipropionate;

-   10.—dioctadecyl 3,3′-thiodipropionate;

-   11.—tris(2,4-di-tert-butylphenyl)phosphate;

-   12.—5 different substances containing the phenyl phosphinite group.

-   13.—Butylhydroxyanisole

Therefore, the problem to be solved by the present invention is toprovide an alternative stable injectable paracetamol solution preventingthe development of an unwanted color of the solution over time.

The solution to this problem is based on the fact that the authors haveidentified that when substances that can react with the p-acetylaminophenolate form, an intermediate chemical species both in thedegradation by deacetylation and in oxidation, these paracetamoldegradation pathways are significantly reduced, a highly stableinjectable paracetamol solution with a minimal content of impuritiesbeing obtained. The reason for this is that the formation ofintermediate products such as gluconated or sulfonated derivatives withthe phenolate form, although they can be unstable in solution,nevertheless significantly reduces paracetamol degradation. Sulfate,gluconate or furfural ions can be found in solution as byproductsgenerated by this degradation.

Therefore, aqueous paracetamol solutions for their use by perfusion ofthe invention comprise a substance that can react with phenolatesturning them into their O-derivatives or coordination compounds. In apreferred embodiment of the invention, such agents are selected from thegroup consisting of reducing sugars such as glucose, galactose,fructose; the acid forms of these sugars or their salts, such asgluconate, glucuronate, glucoheptanoate, galactate; chemical speciescontaining sulfur in an oxidation state less than +6, sodiumformaldehyde sulfoxylate, sulfites or thiourea or any combination of theprevious substances. These compositions produce a solution with veryreduced levels of impurities and the absence of color in the solutionfor long time periods, being able to be stored in antioxidant-freeplastic materials.

It is possible to find aqueous paracetamol formulations for perfusioncontaining antioxidants in the prior art. However, there is no knowndocument studying the different antioxidant power of differentsubstances through the reactivity of phenolate in aqueous solution orits possible practical consequences. The authors have now found that theaction on this intermediate product in the paracetamolhydrolysis/oxidation process allows providing different degrees ofprotection of paracetamol against oxidation in the same pH conditions,such that it is possible to obtain a solution with the aforementionedadvantages by suitable selecting the antioxidant or substance that canreact with the intermediate phenolate form.

On the other hand, it is known that phenols can generate complexes withmetal ions by means of their phenolate form, therefore this fact canalso be used to prevent the occurrence of oxidized forms of paracetamol.The formation of metal complexes with phenolate ions can affect the endresult for obtaining a stable and colorless paracetamol solution and itis necessary to consider this effect because although generally all ofthem case a bathochromic effect in the absorption of radiation ofparacetamol, shifting the absorption towards more colored area of thespectrum, not all of them do so to the same extent: in the case ofcations causing the formation of colored complexes with the phenolateform, as may be the case of iron or zinc, their presence must beprevented by means of adding a suitable chelating agent to thecomposition, whereas those cations producing colorless forms such asmagnesium will favor the stability of the solution since they act asscavengers of the phenolate ions produced.

A very important factor to be considered is that an equilibrium must beachieved between solution color/impurities from paracetamol degradationand impurities from the degradation of the substances used asstabilizers: Although the prior art has described aqueous paracetamolsolutions for perfusion comprising glucose as an isotonic agent, it ishowever necessary to use amounts of the order of 5% m/v to provideisotonicity to the solution, with which amounts a colored solution isobtained after a few months of its production, therefore these solutionswould not be suitable in the present invention. It is thereforenecessary to use the suitable amount for each stabilizing compound sothat said compound shows its stabilizing effect without developing anysubstantial color over time.

A last factor to be taken into account is that the solubility ofparacetamol in aqueous medium is of the order of 12 mg/ml at atemperature of 20° C. and 8 mg/ml at 4° C., such that the process orcomposition of the solution must prevent the crystallization ofparacetamol. This effect is solved by means of filtering the solutionthrough a pore size of 0.45 microns or less, or adding a solubilizingagent as described in international publication WO03033026 issued toBIOREN S. A., disclosing an aqueous paracetamol solution obtained bymixing paracetamol and propylene glycol in citrate medium at a pHcomprised between 4.5 and 6.5 and heating said solution at a temperaturebetween 70° C.-130° C.

EXAMPLES

To study the protective effect of different substances which may have anantioxidant activity providing the stability of the paracetamolsolution, solutions with a variable composition have been made andstored in glass and PVC (poly(vinyl chloride)) materials to latersubject them to wet heat sterilization, which is the safest currentlyadmitted process for injectable solutions.

1) Solutions Stored in Glass Containers

It has been verified that the most stable pH range for paracetamolsolutions is between 4.5 and 6.0 and this has been the pH range used forthe tests carried out, the buffer agents with a pKa close to this pHrange being more favorable because they allow maintaining the optimal pHvalue in a more constant manner. To that end, it is possible to usebuffer agents based con citrates, malates, acetates, lactates,gluconates; and those showing synergistic antioxidant activity such asthose containing citric or malic are more favorable.

The following tests have been carried out as tests for evaluating thestability of the solution:

-   -   Visual appearance.    -   Measurement of the absorbance at 320 nm and 500 nm in 10 mm        thick quartz cells.    -   Content of impurities by means of liquid chromatography based on        the chromatographic conditions of the European Pharmacopoeia 5th        Edition, comparing the relative area with an external        paracetamol standard with a known concentration.

After the wet heat sterilization of the solutions obtained, they weresubjected to a heat treatment at 100° C. for the glass-bottled solutionsand at 70° C. for the solutions stored in plastic material.

The stability of the solution in room temperature conditions of productstorage (25° C.) can be predicted by means of observing thecharacteristics of the solutions subjected to these heat treatments atdifferent times, because, as indicated by K. Thomas Koshy, thedegradation kinetics follow the Arrhenius law depending ontemperature/time.

The three characteristics studied, visual appearance, absorbance atdifferent wavelengths and content of impurities, are related to oneanother. The absorbance at 350 nm (yellow) is caused by p-aminophenol,polymerization products, impurities related to the synthesis ofparacetamol and benzoquinoneimines; the absorbance at 500 nm (pinkishbrown) is caused by benzoquinoneimines and their polymerization. Table 1indicates the maximum values for the impurity corresponding to the areaof the chromatographic peak with the highest value, expressed as % withrespect to paracetamol. The sum of all the impurities is indicated as a% total impurity value.

TABLE 1 Sodium acetate and/or citrate-NaCl antioxidant; Samples in glassTest A1 B1 C1 D1 E1 F1 G1 H1 I2 G2 Antioxidant Sodium Fructose ThioureaSodium Curcumin Sodium 0.001% m/V Does not 0.5% 0.02% m/V ascorbatedithionite nitrite sodium contain Glucose sodium formaldehydeformaldehyde sulfoxylate sulfoxylate After wet sterilization inautoclave at 120° C. for 25 minutes Color Virtually Colorless ColorlessColorless Colorless Orangish Colorless Colorless Colorless Colorlesscolorless brown Abs 350 nm 0.156 0.034 0.013 0.009 0.010 0.671 0.0020.000 0.010 0.010 (AU) Abs 500 nm 0.005 0.002 0.003 0.000 0.002 0.1030.000 0.000 0.003 0.001 (AU) Impurities % impurity, 0.26 0.04 0.08 0.0060.15 5.8 0.05 0.12 0.02 0.02 individual maximum value % Total 0.42 0.080.21 0.03 0.24 8.30 0.10 0.18 0.05 0.05 impurities 16 hours at 100° C.Color Abs 350 nm 0.261 0.367 0.162 0.072 0.194 1.896 0.119 0.148 0.0100.027 (AU) Abs 500 nm 0.016 0.041 0.040 0.016 0.047 0.379 0.022 0.0380.003 0.004 (AU) Impurities % impurity, — 0.087 0.29 0.1 0.89 — 0.580.73 0.04% 0.03% individual maximum value % Total — 0.29 0.60 0.22 1.26— 0.86 1.05 0.08 0.08 impurities 24 hours at 100° C. Color Yellow brownBrown Slightly Virtually Slightly Intense Slightly Brown SlightlyVirtually brown colorless brown brown brown brown colorless Abs 350 nm0.420 0.566 0.249 0.096 0.291 — 0.156 0.219 0.134 0.032 (AU) Abs 500 nm0.039 0.074 0.056 0.028 0.078 0.040 0.060 0.044 0.005 (AU) Impurities %impurity, — 0.09 0.32 0.20 1.0 — 0.69 0.81 0.05 0.05 individual maximumvalue % Total — 0.36 0.69 0.34 1.42 — 0.97 1.13 0.11 0.11 impurities

It can be observed that not all the antioxidants stabilize the solutionin the same manner. After sterilization, visually, neither theascorbates nor the nitrites protect paracetamol. The antioxidant-freesolution maintains its colorless appearance; however, theantioxidant-free solution is the one containing the highest values ofimpurities among the colorless solutions. The effect of these substancesas antioxidants just as they are is obviously not enough to stabilizethe solution.

After 16 hours of treatment at 100° C., it is observed that the solutioncontaining dithionite, glucose or sodium formaldehyde sulfoxylate arethe ones with less color, showing values of absorbance at 350 nm thatare less than 0.100 absorbance units and at 500 nm less than 0.020absorbance units.

After 24 hours at 100° C., it can be observed that the formulationcontaining sodium sulfoxylate at a concentration of 0.02% m/V can equalthe stability of the commercial formulation Perfalgan® (obtainedaccording to the process described in the SCR Pharmatop patent), whichformulation, kept in its original glass bottle for 24 hours at 100° C.,remains colorless with virtually nil absorbances at 350 nm and 500 nm.

2) Solutions Stored in Plastic Material

The same conclusions can be obtained if the evolution of the paracetamolsolution in plastic material is observed:

TABLE 2 Sodium acetate and/or citrate - NaCl - antioxidant; Samples inpolyvinyl chloride (PVC) Test T1 T2 T3 Antioxidant Does not 0.5% Glucose0.015% m/V contain sodium formaldehyde sulfoxylate After wetsterilization in autoclave at 120° C. for 25 minutes Color ColorlessColorless Colorless Abs 350 nm (AU) 0.009 0.010 0.008 Abs 500 nm (AU)0.003 0.003 0.001 Impurities % impurity, 0.18 0.02 0.02 individualmaximum value % Total 0.27 0.05 0.06 impurities 48 hours at 70° C. ColorVirtually Virtually Data not colorless colorless available Abs 350 nm(AU) 0.063 0.046 Abs 500 nm (AU) 0.016 0.011 Impurities % impurity, 0.420.06 individual maximum value % Total 0.58 0.09 impurities 89 hours at70° C. Color Brown Virtually Colorless colorless Abs 350 nm (AU) 0.1480.082 0.029 Abs 500 nm (AU) 0.036 0.016 0.000 Impurities % impurity,0.56 0.08 0.05 individual maximum value % Total 0.74 0.13 0.13impurities

Both the color and the content of impurities are significantly lower inthe paracetamol solutions including a suitable antioxidant. Thesesuitable antioxidants are so not because of their antioxidant activitybut because they neutralize paracetamol degradation through thep-acetaminophenolate pathway, which even though its presence is minimalin acid media, its reactivity is significantly higher. The presence ofthe phenolate form is shown in paracetamol compositions containingsodium ion and at a pH=5.0 by means of liquid chromatography and massspectrometry, whereby it is possible to obtain chromatographic peakscontaining the mass corresponding to the formation of the adduct withsodium through phenolate.

The studied compositions have a much higher stability than that ofPerfalgan® when it is stored in plastic material. The Perfalgan®solution in PVC thus has an intense grayish brown color after it is keptfor 67 hours at 70° C. with an absorbance of 0.267 AU at 350 nm and of0.38 AU at 500 nm.

3) Comparison of Solutions Stored in Different Types of Materials

The effect on the color of the same chemical composition according toits storage in different plastic materials (polyolefins and PVC), inwhich polyvinyl chloride is favored, is observed in the followingexample.

TABLE 3 Paracetamol solution Color/Absorbance at 350 nm 3.3%citrate-acetate- Gluconate- glucose malic Solution stored in inPolyolefin in PVC in PVC After wet sterilization in autoclave at 120° C.for 25 minutes Color Colorless Colorless Colorless Abs 350 nm (AU) 0.0160.026 0.017 After treatment for 134 hours at 65° C. Color VirtuallySlight Colorless colorless color Abs 350 nm (AU) 0.074 0.098 0.036

The concentration of antioxidant has an important role in thestabilization of the solution because the degradation of suchantioxidant in turn generates impurities providing color to thesolution. In the case of sugars, they can produce other furfurals andgluconated derivatives, in the case of reducing substances with sulfur,they can produce sulfonated derivatives of paracetamol which can in turnalso provide color to the solution, or the inorganic form of sulfates.Depending on the type of stabilizing substance of the solution, itsoptimal concentration varies: reducing sugars have an optimal effectbetween 0.5% and 3.0% m/v, sodium formaldehyde sulfoxylate have anoptimal effect between 0.001% and 0.02% m/v. It is also observed thatthe use of the acid form of glucose also prevents the occurrence ofcolor.

As a result, it is possible to obtain a stable paracetamol solution bymeans of incorporating in the solution antioxidant substances that canreact with p-aminophenolates giving rise to their O-derivatives orcoordination compounds, preferably selected from the group consisting ofreducing sugars such as glucose, galactose, fructose; acid forms of thesugars or their salts such as lactobionate, gluconate; glucuronate;glucoheptanoate, galactate, lactobionate or lactones such asgluconolactone; chemical species containing sulfur in an oxidation stateless than +6, sodium formaldehyde sulfoxylate, sulfites or thiourea, andit is possible that these substances can produce derivatives with thephenolate form of paracetamol. Injectable paracetamol solutions with acontent of impurities that is less than 0.1% can thus be obtained. Thesolutions of the invention further have the advantage that they can becontained in glass bottles or bottles of any other type of plasticmaterials including PVC, and they can be sterilized by heat orfiltration.

1. An aqueous paracetamol solution for its use by perfusion with a pHbetween 4.5 and 6.0, comprising at least one substance that can reactwith phenolates giving rise to its O-derivatives or other coordinationcompounds.
 2. An aqueous paracetamol solution according to claim 1, inwhich the pH is between 5.0 and 5.5.
 3. An aqueous paracetamol solutionfor perfusion according to claim 1, in which the substance that canreact with phenolates is selected from the group consisting of sugarssuch as glucose, galactose, fructose, acid forms of the sugars or theirsalts such as gluconate, glucuronate, glucoheptanoate, galactate,lactobionate or lactones such as glucunolactone or chemical speciescontaining sulfur in an oxidation state less than +6 such as sodiumformaldehyde sulfoxylate, sulfites or metal cations or any combinationof the previous substances.
 4. An aqueous paracetamol solution forperfusion according to claim 1, in which the substance that can reactwith phenolates is glucose, gluconate, lactobionate, gluconolactone,sodium formaldehyde sulfoxylate, sodium bisulfite or any combination ofthe previous substances.
 5. An aqueous paracetamol solution forperfusion according to claim 1, in which the substance that can reactwith phenolates is glucose at a concentration between 0.5% and 3.0% m/v.6. An aqueous paracetamol solution for perfusion according claim 1, inwhich the substance that can react with phenolates is sodiumformaldehyde sulfoxylate at a concentration between 0.001% and 0.02%m/v.
 7. An aqueous paracetamol solution for perfusion according to claim1, further comprising a chelating agent.
 8. An aqueous paracetamolsolution for perfusion according to claim 1, comprising forms ofsaccharic acids or sulfates or furfurals as a result of the degradationof the substance that can react with phenolates.
 9. An aqueousparacetamol solution for perfusion according to claim 1, which can besterilized by heat or by filtration.